Download Investigation of nausea

PEER REVIEWED FEATURE
2 CPD POINTS
CLINICAL INVESTIGATIONS FROM THE RACP
Investigation
of nausea
How far to go
before referral
ELIOT ROACH
MB BS(Hons), FRACP, GESA
In this series, we present authoritative advice on
the investigation of a common clinical problem,
especially commissioned for family doctors and
written by members of the Royal Australasian
College of Physicians.
• Nausea is a common presenting symptom and is often
idiopathic or functional.
• Organic causes are usually apparent from a patient’s
history and physical examination.
• A few basic investigations will rule in or out most underlying
causes.
• Referral of patients to a gastroenterologist should be
considered when the diagnosis is in doubt, there is the
suspicion of an underlying gastrointestinal cause or to
reassure the patient.
• Consider anxiety as an underlying or contributing factor
to nausea.
MedicineToday 2015; 16(7): 40-44
Dr Roach is a Gastroenterologist in private practice at Sydney Adventist
Hospital, Sydney, NSW.
SERIES EDITOR: Christopher S. Pokorny, mb bs, fracp, frcp, facg, is Conjoint
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PM Page
Associate Professor of Medicine
at _Layout
the University
of New South
and 4
Visiting Gastroenterologist, Sydney and Liverpool Hospitals, Sydney, NSW.
40 MedicineToday
N
ausea is the sensation of feeling sick or wanting to vomit.
It should be distinguished from other symptoms such
as fullness, satiety, bloating and dyspepsia, which the
patient may interpret as nausea. Most cases of nausea
do not have a serious cause but the symptom can be bothersome
and in some cases debilitating. Treatment options are limited,
have variable efficacy and in some cases are unsuccessful. Often
the nausea will resolve without treatment.
Neurophysiology of nausea
Nausea may arise from the gut directly – for example, from food
poisoning or gastritis – or from the central nervous system – for
example, due to motion sickness or alcohol intoxication. The
neural pathways involved in nausea are probably the same as
those that cause vomiting. These include the chemoreceptor
trigger zone in the brainstem, which is sensitive to c­ hemical and
neuropeptide stimulation, and the vomiting centre on the floor
of the fourth ventricle of the brain, which receives input from
the chemoreceptor trigger zone, vagal and sympathetic afferents
from the gastrointestinal tract and the cortex, hypothalamus
and limbic system. Efferent neural impulses travel from the
vomiting centre via the vagus, phrenic and spinal nerves to cause
retching and vomiting.
During nausea, gastric myoelectric activity is disturbed
­causing reduced gastric tone and peristalsis. Antinausea
­medications may act centrally, such as prochlorperazine, or
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KEY POINTS
peripherally, such as domperidone, or sometimes at both sites,
such as metoclopramide.
Clinical assessment of the patient with nausea
The patient with nausea may be of any age. The pattern of
symptoms and clinical course provide the best clues to
­establishing whether the nausea is organic, functional or drug
related.
Aetiologically, nausea can originate from the gastrointestinal
tract, the central nervous system or from toxic, metabolic
or medication-related causes. It is important to define the onset
and periodicity of symptoms, whether they are persistent
or intermittent, their variability, and precipitating or relieving
factors.
Associated symptoms such as headache, dizziness, vertigo
and diplopia would point to a neurological cause. ­Dyspepsia,
abdominal pain, bloating, heartburn, dysphagia, diarrhoea,
constipation and/or weight loss would indicate a gastroenterological diagnosis. Onset of nausea after starting a new medication would point to the drug being the cause.
Nausea may be the presenting symptom in a patient with
anxiety or depression, so it is important to take a psychosocial
history.
Differential diagnosis
The more common causes of nausea are listed in the Box. Many
of the causes will be obvious from the patient’s symptoms and
signs.
Functional nausea
Most cases of chronic nausea have a functional aetiology.
Chronic nausea is usually mild or moderate in severity, often
worse in the morning and may improve during the day. It can
be intermittent, with good and bad days or longer periods of
remission between symptomatic episodes. Some patients develop
nausea after eating but in many there may be no obvious precipitating factors. Nausea may be associated with or pre­cipitated
by anxiety and stress. Generally, weight loss is not a feature,
unless there is avoidance of food and therefore reduced caloric
intake. Patients with functional nausea will often have spontaneous remissions and exacerbations.
Patients with functional nausea may also have functional
dyspepsia (i.e. early satiety, epigastric pain and bloating) and/or
symptoms of irritable bowel syndrome. These may coexist or
alternate at different times.
Drug-induced nausea
Any recently introduced medication should be suspected as the
cause of the nausea. Table 1 shows a list of drugs that can induce
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COMMON CAUSES OF NAUSEA
Functional nausea
Idiopathic, the patient looks well and examination is normal,
may be associated with nonulcer dyspepsia or irritable
bowel syndrome
Infections
Gastroenteritis, Helicobacter pylori, systemic infections
Gastrointestinal
Peptic ulcer, oesophagitis, gastric cancer, colitis/Crohn’s disease,
constipation, gastric outlet obstruction, gastroparesis, hepatitis,
cholangitis, liver cancer, intra-abdominal carcinomatosis,
cholecystitis, pancreatitis, intestinal pseudo-obstruction
Central nervous system
Labyrinthine disorders, tumours, elevated intracranial pressure,
demyelination, cranial irradiation
Endocrine
Pregnancy, uraemia, hyperparathyroidism, hyperthyroidism,
Addison’s disease, diabetic ketoacidosis
Other
Abdominal radiotherapy, hepatic congestion (congestive
cardiac failure), myocardial infarction
Anxiety
Drug-induced
See Table 1 for a list of drugs that can cause nausea
Investigation of patients with nausea
Functional nausea is idiopathic and is a diagnosis of exclusion,
so the GP must decide how far to investigate. Younger patients
require less investigation than older patients, in whom organic
disease is more likely. Physical examination of patients with
nausea typically has normal results, but clues to an organic
aetiology are hepatomegaly or hepatosplenomegaly, an abdominal
mass, lymphadenopathy, clubbing, significant weight loss, pallor,
jaundice or skin pigmentation.
After assessing the patient clinically, the GP must decide
whether to reassure the patient and take an expectant observational approach, to investigate further or to refer the patient to
a specialist.
Blood tests
Basic blood tests will detect most inflammatory, metabolic and
neoplastic disorders. These tests should include a full blood
count, multiple biochemical analysis, coeliac serology, breath
test for Helicobacter pylori and measurement of C-reactive
­protein, thyroid-stimulating hormone, calcium and blood sugar
levels and erythrocyte sedimentation rate. Occasionally, a patient
with hepatic metastases or systemic disease may have normal
blood test results.
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Investigation of nausea continued
Testing for tumour markers is not recommended as the
diagnostic and predictive value is low. These tests should be
reserved for patients with known diseases or to help pinpoint
tumours with an uncertain primary origin.
Imaging
Some x-rays and scans can help diagnose the cause of nausea.
• Plain abdominal x-ray may show faecal loading, colonic
pseudo-obstruction or a dilated stomach.
• Abdominal ultrasound is noninvasive and is an excellent
way of imaging the liver, gall bladder, spleen and pancreas
(which is sometimes obscured by stomach gas); it does not
detect intraluminal pathology (e.g. colorectal cancer or a
peptic ulcer).
• Abdominal CT scan may be an alternative to ultrasound
but is more expensive. This should be reserved for patients
with a higher suspicion for organic disease, such as
­hepatomegaly, an abdominal mass, abnormal liver f­ unction,
anaemia or Crohn’s disease. Generally, CT scans should be
avoided in younger patients because of the r­ adiation risk.
• Brain CT or MRI scans should be performed in patients
with neurological symptoms to assess for an underlying
tumour or degenerative or inflammatory brain disorders.
• Abdominal MRI scans are not required to investigate
patients with nausea except when CT is contraindicated or
to further evaluate a lesion detected on ultrasound or CT
scan; no Medicare rebate is available for this indication.
• Radionuclide gastric emptying scans are used to
investigate patients with suspected gastroparesis and are
only occasionally helpful in patient management.
• Hepatobiliary iminodiacetic acid (HIDA) scans are likely
to be useful only if the patient has biliary features
(right upper quadrant pain).
• Barium meals and enemas are likely to be helpful only in
selected cases, and generally endoscopy and colonoscopy
are preferable.
• Manometry is a rarely performed investigation restricted
to specialty motility units; it is usually used for the work up
of patients with gastroparesis in whom a gastric pacemaker
is being considered.
When to refer
Some GPs will refer their patient with nausea immediately to a
gastro­enterologist and others will conduct a full work up of the
patient and then refer the patient on if the problem remains
unresolved. This is an individual judgement but referral of the
patient to a gastro­enterologist should be considered when the
diagnosis is not clear, when there is suspected or proven organic
disease, or when the patient or GP want another opinion about
the diagnosis or treatment.
Endoscopy of the upper gastrointestinal tract is sometimes
performed, especially in patients older than 40 years of age.
Some patients will have unsuspected ulcerative oesophagitis, moderate-to-severe gasTABLE 1. DRUGS THAT CAN INDUCE NAUSEA*
tritis, an ulcer or rarely a tumour. A normal
Class
Drugs
result can be reassuring for the patient.
Negative r­ esults on investigations, including
Antibiotic
Erythromycin, metronidazole, sulfonamide, tinidazole and
blood tests, ultrasound and endoscopy,
most others
would generally confirm the clinical suspiAnticonvulsants
Carbamazepine, phenytoin, sodium valproate
cion of functional nausea, and the patient
should be reassured that there is no need
Anti-inflammatory
Colchicine, mesalazine, sulfasalazine
for further investigation unless their sympAnti-Parkinson
Bromocriptine, L-dopamine
toms change.
Biguanide
Metformin
Cardiac
Antiarrhythmics, beta blockers, calcium channel blockers,
digoxin, diuretics
Chemotherapy
Cisplatin, doxorubicin, etoposide, 5-fluorouracil, vinblastine
Hormones
Anti-androgens, oestrogens, oral contraceptive pill, tamoxifen
Immunosuppressive
Azathioprine, mercaptopurine, methotrexate
NSAIDs, COX-2
inhibitors
Aspirin, celecoxib, diclofenac, ibuprofen, meloxicam,
naproxen
Opioids
Codeine, fentanyl, morphine, oxycodone, tramadol
Sulfonylurea
Glipizide
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* Listed alphabetically by class.
42 MedicineToday
Treatment of nausea
There are many drugs available for the treatment of patients with nausea. Table 2 lists
some of these drugs, how they act and any
side effects that may occur.
Metoclopramide and prochlorperazine
are suitable for short-term use. N
­ ote that
younger patients have a higher incidence
of acute dystonia as a side effect of these
drugs. They should not be used long term
because of the risk of tardive dyskinesia.
Droperidol, haloperidol and chlorpromazine can be used in patients with nausea
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TABLE 2. MEDICATIONS USED IN THE TREATMENT OF NAUSEA*
Drug
Class
Action
Side effects
Notes
Amitriptyline,
nortriptyline
Tricyclic
antidepressant
Antihistamine;
anticholinergic; serotonin
reuptake inhibitor
Dry mouth; lethargy;
somnolence
Used to treat functional
nausea/dyspepsia and
anxiety
Aprepitant,
fosaprepitant
Neurokinin receptor
antagonist
NK1 blocker
Used to treat nausea
associated with
chemotherapy (with
ondansetron and
corticosteroids)
Cannabinoids
Possibly reduces central
5-HT release
Dysphoria; xerostomia;
psychoactive effects;
hypotension; drowsiness
Used to treat nausea
associated with
chemotherapy (not TGA
approved)
Chlorpromazine or Phenothiazine
prochlorperazine
Central D2 inhibition
(M1 and H1 inhibition)
Sedation; anticholinergic
side effects; acute dystonia
(young patients);
hypotension; tardive
dyskinesia (long-term use)
Used to treat acute nausea of
any cause and migraine
Cisapride
Serotonergic
Peripheral 5-HT4 agonist;
prokinetic
Cardiac arrhythmias;
prolonged QT interval; drug
interactions; diarrhoea;
cramps
Only available through the
TGA Special Assess Scheme;
not available on the PBS
Diphenhydramine
Antihistamine
Central H1 blockade
Drowsiness
Used to treat motion sickness
and vestibular nausea
Domperidone
Benzamide
Peripheral D2 inhibition
(minimally crosses the
blood–brain barrier)
Headache; prolonged QT
interval; drug interactions;
hyperprolactinaemia (rare)
Used to treat acute nausea of
any cause and migraine
Droperidol,
haloperidol
Butyrophenone
(phenothiazine-like)
Central D2 inhibition
Side effect profile is high;
same as for phenothiazines
Second-line treatment;
short-term use
Ginger
Peripheral and central
action of gingerols and
shogaols
Used in pregnancy (can also
use vitamin B 6 ) and to treat
motion sickness
Hyoscine or
scopolamine
Anticholinergic
Central M1 blockade
Drowsiness; dry mouth
Used to treat motion sickness
Metoclopramide
Benzamide
Central and peripheral D2
inhibition (weak 5-HT3
blocker); cholinergic
stimulation of gastric muscle
Akathisia; anxiety; acute
dystonia in young patients;
extrapyramidal side effects
(long-term use)
Used to treat acute nausea of
any cause and migraine
Ondansetron
Antiserotonin
Serotonin (5-HT3)
antagonist
Constipation; headache;
asthenia
Used to treat nausea
associated with
chemotherapy (PBS
restricted) and hyperemesis
gravidarum
Promethazine
Antihistamine/
phenothiazine
Central H1 blockade
Same as for phenothiazines Used to treat motion sickness
and hyperemesis gravidarum;
second-line treatment for
nausea
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* Listed alphabetically by drug name. Abbreviations: D2 = dopamine 2; H1 = histamine 1; 5-HT = 5-hydroxytryptamine; M1 = muscarinic 1; NK = neurokinin.
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43
Investigation of nausea continued
that proves resistant to treatment, but the side effect profile is
high and includes P
­ arkinsonism, sedation, postural hypotension
and dyskinesia. These drugs should only be used in the short
term.
Domperidone is a peripheral dopamine antagonist with poor
blood–brain barrier penetration. It is generally safe, but there has
been a recent warning regarding cardiac arrhythmias. These are
uncommon but can occur in patients taking more than 30 mg/day
or in those with cardiac conduction defects, and domperidone
interacts with medications that prolong the QT interval.
The antihistamines promethazine and diphenhydramine
can be effective second-line treatments for patients with nausea,
but sedation can be a problem. They are useful for the treatment
and prevention of motion sickness.
Ondansetron is used predominantly to treat patients with
nausea from chemotherapy and those with other drug-induced
nausea and vomiting. It is listed on the PBS with authority for
the management of nausea and vomiting associated with radio­
therapy being used to treat malignancy or nausea and vomiting
associated with cytotoxic chemotherapy being used to treat
malignancy which occurs within 48 hours of chemotherapy
administration. However, it is not reimbursed on the PBS for
other indications and is expensive.
If anxiety and insomnia are associated features of nausea,
low-dose tricyclic antidepressants, such as amitriptyline or
nortriptyline 10 to 25 mg at night, can occasionally be effective
for treating patients with functional upper gut symptoms, including nonulcer dyspepsia and nausea. However, they should be
considered second-line treatments. The anticholinergic side
effects can limit the use of tricyclic antidepressants.
Conclusion
Nausea is a common clinical presentation. If the patient’s clinical
history and examination are normal and the patient appears
well, then usually the diagnosis will be functional or idiopathic
nausea. This is a diagnosis of exclusion and a few basic tests will
often rule out serious pathology. Treatment can involve reassurance and short- or long-term medications, but in some patients
nausea becomes chronic/refractory and medications are ineffective. The possibility of organic pathology, such as cancer,
inflammatory diseases, drug side effects and central nervous
system causes of nausea, should always be considered. Nausea
can be the main manifestation of anxiety and this diagnosis
should be considered in all patients where no other cause is
obvious. It is important not to over-investigate unnecessarily
when initial basic investigation results are normal because this
may lead to unnecessary worry, waste time and money, and
suggest to the patient that there is a rare or missed diagnosis.
Often a period of observation will result in improvement in
symptoms and confirm the nonserious nature of the nausea.
I would give the patient who does not have worrisome symptoms or signs a month or two of observation and then reassess
them. Then investigate with some basic tests if they are no better.
I would investigate anyone over the age of 40 years early and/or
refer them to a specialist. MT
Further reading
Lee M, Feldman M. Nausea and vomiting. In: Sleisenger M, Fordtran J, eds.
Gastrointestinal disease. 5th ed. Philadelphia: WB Saunders; 1993.
pp. 509-518.
Longstreth GF. Approach to the adult with nausea and vomiting. In: Talley NJ,
Grover S, eds. UptoDate. Wolters Kluwer; 2014. Available online at:
http://www.uptodate.com/contents/approach-to-the-adult-with-nausea-andvomiting (accessed July 2015).
Longstreth GF, Hesketh PJ. Characteristics of antiemetic drugs. In: Talley NJ,
Grover S, eds. UptoDate. Wolters Kluwer; 2014. Available online at:
http://www.uptodate.com/contents/characteristics-of-antiemetic-drugs
(accessed July 2015).
Longstreth GF, Lacy BE. Functional dyspepsia in adults. In: Talley NJ, Grover S,
eds. UptoDate. Wolters Kluwer; 2014. Available online at: http://www.
uptodate.com/contents/functional-dyspepsia-in-adults (accessed July 2015).
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